Synthesis of 4,5-Dihydropyrazoles via Palladium-Catalyzed Cyclization Reactions of β,?3-Unsaturated Hydrazones with Aryl Iodides

Article abstract of DOI:10.1021/acs.organomet.9b00656

A novel two-component cyclization toward the synthesis of polysubstituted 4,5-dihydropyrazoles was carried out: i.e., cyclization of β,?3-unsaturated hydrazones with aryl iodides catalyzed by Pd(0). The reaction forms new carbon-carbon bonds and carbon-ni

Full text of DOI:10.1021/acs.organomet.9b00656

Communication
pubs.acs.org/Organometallics
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Synthesis of 4,5-Dihydropyrazoles via Palladium-Catalyzed
Cyclization Reactions of β,γ-Unsaturated Hydrazones with Aryl
Iodides
Rongcai Ding, Rongmei Lu, Zixuan Fang, Yanjun Liu, Shaoyu Wang, Xiaoxia Liang, Cheng Zhang,
Tianyi Huang, and Jinxing Hu*
School of Pharmacy, Weifang Medical University, Weifang 261053 People’s Republic of China
S
* Supporting Information
ABSTRACT: A novel two-component cyclization toward the
synthesis of polysubstituted 4,5-dihydropyrazoles was carried
out: i.e., cyclization of β,γ-unsaturated hydrazones with aryl
iodides catalyzed by Pd(0). The reaction forms new carbon−
carbon bonds and carbon−nitrogen bonds with moderate to
good reactivity.
azoles through halocyclization with β,γ-unsaturated hydrazones
ive-membered nitrogen heterocycles are an important
Fclass of compounds that are widespread in natural and N-bromosuccinimide (Scheme 1, eq 2).4 Afterward,
products, bioactive molecules, and drugs.1 Dihydropyrazoles
Nicolini’s group reported a copper-catalyzed interceptive [4
+ 1] annulation of 1,2-diaza-1,3-dienes with diazo esters,
leading to substituted 4,5-dihydropyrazoles (Scheme 1, eq 3).5
In recent years, metal-catalyzed functional grouping of
allenes to synthesize various heterocyclic compounds has
become a research hotspot.6−10 In particular, the study of
pyrazoline compounds remains a challenge for researchers. In
our study on allene chemistry, we have demonstrated that
allenes with nucleophilic functional groups are common
building blocks for the synthesis of potentially important
heterocyclic compounds, such as imidazolidines.11 Here we
wish to report our most recent observation on the Pd-catalyzed
cyclization for the synthesis of polysubstituted dihydropyr-
azoles from β,γ-unsaturated hydrazones and aryl iodides
(Scheme 1, eq 4).
and their derivatives have been found to show a diverse range
of biological activities, including anticancer, antiviral, and
antidiabetic activities and blood pressure lowering effects.2
After years of research, scientists have discovered a number of
methods to synthesize dihydropyrazoles.
̀
Briere’s group adopted enantioselective phase-transfer
catalysis to synthesize pyrazolines (Scheme 1, eq 1).3 Xiao’s
group explored a new strategy to synthesize 4,5-dihydropyr-
Scheme 1. Selected Synthetic Methods for
Dihydropyrazoles
On the basis of the results of previous experiments, we
attempted the reaction of β,γ-unsaturated hydrazones and aryl
iodides under identical conditions (conditions: 1a (1.0 equiv),
aryl halide (1.2 equiv), Pd(PPh3)4 (5 mol %), K2CO3 (1.5
equiv), THF under reflux) (Table 1, entry 1). During
screening, 4,5-dihydropyrazole 3aa was obtained in 58%
isolated yield. Compound 3aa was fully characterized by
1H/13C NMR, MS, and HRMS methods. Subsequently, on the
basis of previous research, we tested a number of Pd catalysts.
As expected, the yields obtained with other Pd catalysts were
reduced by different levels (Table 1, entries 2−4). We also
found that the reaction did not proceed in the absence of Pd
catalyst (Table 1, entry 5). Afterward, we investigated the
effect of various bases on the reaction yield (Table 1, entries
6−11). Among them, Cs2CO3 promoted the reaction effect the
best (Table 1, entry 8). Then, we tested the effectiveness of
Received: October 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.9b00656
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Communication
a
a,b
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope of Aryl Iodides.
b
entry
cat.
base
solvent
yield (%)
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(CF3COO)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
CsF
Cs2CO3
t-BuOLi
NaOH
NaH
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
dioxane
DCM
DMF
CH3CN
CH3CN
CH3CN
58
46
43
50
n.d.
31
20
65
21
trace
32
c
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
9
10
11
12
13
14
15
16
17
18
53
65
trace
53
67
d
70
e
68
a
Reaction conditions: under a N2 atmosphere, 1a (0.20 mmol, in 3
mL of CH3CN), PhI (1.2 equiv), base (1.5 equiv), and [Pd0] (5 mol
%) at reflux. Isolated yields. n.d. = not detected. Reaction carried
out in a tube with a screw cap in 90 °C. Reaction carried out in a
tube with a screw cap in 110 °C.
b
c
d
e
several solvents on the reaction outcome (Table 1, entries 12−
16) and achieved the optimal results with CH3CN (Table 1,
entry 16). Subsequently, we investigated the effect of the
reaction temperature on the yield (Table 1, entries 16−18).
Finally, the standard reaction conditions used for further
investigations were established as 1a (1 equiv), 2a (1.2 equiv)
with Cs2CO3 (1.3 equiv) in CH3CN at 90 °C with
[Pd(PPh3)4] (5 mol %) as the catalyst.
The results of the coupling cyclization of 1a with other
differently substituted aryl halides 2 under Pd(0) catalysis and
the standard conditions are summarized in Scheme 2.
Among the substrates, disubstituted halides gave a much
lower reaction yield. As can be seen from Scheme 2, electron-
donating (Scheme 2, 3ab−af) and electron-withdrawing
substituents (Scheme 2, 3ag−aj) on the benzene ring were
well tolerated under the cyclization conditions. It was also
found that the reaction outcome was better when electron-
donating substituents were present on the phenyl ring
(Scheme 2, 3ab−af). Moreover, the reaction effect of the
dihalogen substitution was lower than that of the monohalogen
substitution: for example, the reaction yield of 3aj was lower
than that of 3ag. The reaction proceeded smoothly even when
a sensitive group was present on the phenyl ring (Scheme 2,
3ak,al). In addition, when a strongly electron withdrawing
group such as CF3 was present on the benzene ring, the
corresponding pyrazoline derivative 3am was obtained in 58%
yield. Finally, we studied the effect of heterocyclic substitution
on the cyclization and obtained the corresponding thiophene-
and naphthalene-substituted pyrazoline compounds 3an,ao in
83% and 80% yields, respectively. In addition, we also
a
Reaction conditions: under a N2 atmosphere, 1a (0.20 mmol, in 3
mL of CH3CN), Pd(PPh3)4 (5 mol %), 2 (1.2 equiv), and Cs2CO3
b
(1.5 equiv). Isolated yields.
investigated the reaction of phenyl bromide or phenyl triflate
with 1a to obtain the desired compound 3aa in a moderate
yield. Surprisingly, 1a reacted with vinyl iodide to produce the
corresponding compound 3ap; the yield increased to 85%.
From the above results, we conclude that aryl iodides are good
ligands, which could generate various pyrazoline derivatives
with potential biological activity.
Subsequently, we investigated the cyclization of different
substituted β,γ-unsaturated hydrazones (1) and iodobenzenes
(2a). Irrespective of the presence of electron-withdrawing
(Scheme 3, 3ba−da) or electron-donating substituents
(Scheme 3, 3ga), the reactions afforded the corresponding
pyrazoline derivatives. Even substrates bearing strongly
electron withdrawing groups such as CF3 (Scheme 3, 3ea)
B
DOI: 10.1021/acs.organomet.9b00656
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Communication
hinder the cyclization, and it was revealed that the reaction did
not proceed via a radical mechanism.
Scheme 3. Substrate Scope of β,γ-Unsaturated
Hydrazones
a b
,
a b
,
Scheme 4. Mechanistic Studies
a
Reaction conditions: under a N2 atmosphere, 1 (0.20 mmol, in 3 mL
of CH3CN), Pd(PPh3)4 (5 mol %), 2a (1.2 equiv), and Cs2CO3 (1.5
b
equiv). Isolated yields.
On the basis of previous research,6−11 we propose a possible
reaction mechanism in Scheme 5. Initially, Pd(0) reacts with
Scheme 5. Proposed Mechanism
a
Reaction conditions: under a N2 atmosphere, 1 (0.20 mmol, in 3 mL
of CH3CN), Pd(PPh3)4 (5 mol %), 2a (1.2 equiv), and Cs2CO3 (1.5
b
equiv). Isolated yields.
and CN (Scheme 3, 3fa) gave the target compounds in 65%
and 68% yields. It is worth mentioning that thiophene-
substituted β,γ-unsaturated hydrazone can also form pyrazoline
derivative (Scheme 3, 3ha) in 55% yield, thereby expanding
the application of the method. In addition, we changed the
terminal substituents of the β,γ-unsaturated hydrazones to
investigate the effect of different substituents on the reaction
outcome.
This procedure was also applicable to the reaction of β,γ-
unsaturated hydrazones with different substituted protective
groups and aryl iodides under the standard conditions: boc
(3ia, 73%) and acetyl (3ja, 64%) analogues were isolated in
moderate yields. When the terminal ester group was replaced
with a sulfonyl group, the reaction did not proceed smoothly.
(Scheme 3, 3ka). Subsequently, the effect of removing the
terminal substituents on the reaction outcome was investigated
(Scheme 3, 3la). In this case, the reaction did not proceed
smoothly, revealing the importance of terminal protective
group substitution. Finally, replacement of unsaturated
hydrazones with unsaturated oximes led to a smooth reaction
(Scheme 3, 3ma−oa). This provides a new synthesis route to
4,5-dihydroisoxazole derivatives.
the aryl iodide to give oxidative addition product A. Then, the
allene double bond is coordinated with the electrophilic
complex A and subsequent carbopalladation affords the
intermediate B. Afterward, B initiated by intramolecular attack
of the lone pair electrons by the imine nitrogen affords the
intermediate C. Subsequently, amine complex C reacts with
base to generate the intermediate D. The last, resulting
complex D undergoes reductive elimination to afford the target
pyrazoline 3, while releasing the Pd(0) catalyst for the next
cycle.
In summary, we have developed an efficient method for the
synthesis of polysubstituted 4,5-dihydropyrazole and 4,5-
dihydroisoxazole derivatives. The experimental results showed
that a variety of substituents were well tolerated in this
method. This study provides a novel synthesis route to
nitrogen-containing heterocycles and potentially bioactive
compounds. Further research aimed at expanding the
applications of this method is underway in our laboratory.
On the basis of the above experimental results, we attempted
to elucidate the mechanism of the reaction. According to
previous research,9,11 we attempted to add radical scavengers
(TEMPO, BHT) to study their effect on the reaction (Scheme
4, eqs 1 and eq 2). The addition of these scavengers did not
C
DOI: 10.1021/acs.organomet.9b00656
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Reaction for One-pot Highly Stereoselective Synthesis of (Z)-α-
Hydroxymethyl Allylic Sulfones. Adv. Synth. Catal. 2018, 360, 631−
636.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.9b00656.
■
S
(10) For recent reviews see: Mascarenas, J. L.; Varela, I.; Lopez, F.
Allenes and Derivatives in Gold(I)- and Platinum(II)-Catalyzed
Formal Cycloadditions. Acc. Chem. Res. 2019, 52 (2), 465−479.
Huang, X.; Ma, S. Allenation of Terminal Alkynes with Aldehydes and
Ketones. Acc. Chem. Res. 2019, 52, 1301−1312. Yang, B.; Qiu, Y.
Control of Selectivity in Palladium(II)-Catalyzed Oxidative Trans-
formations of Allenes. Acc. Chem. Res. 2018, 51 (6), 1520−1531.
Jiang, X. P.; Fu, C.; Ma, S. Highly stereoselective iodolactonization of
4,5-allenoic acids - an efficient synthesis of 5-(1’-iodo-1’(Z)-alkenyl)-
4,5-dihydro-2(3H)-furanones. Chem. - Eur. J. 2008, 14 (31), 9656−
9664. Ma, S. Transition metal-catalyzed/mediated reaction of allenes
with a nucleophilic functionality connected to the alpha-carbon atom.
Acc. Chem. Res. 2003, 36, 701−712. Dorel, R.; Grugel, C. P.; Haydl, A.
M. The Buchwald-Hartwig Amination After 25 Years. Angew. Chem.,
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Experimental procedures, full spectroscopic data for all
new compounds, and of 1H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail for J.H.: jinxinghu2013@wfmc.edu.cn.
ORCID
Jinxing Hu: 0000-0002-1533-7146
Notes
The authors declare no competing financial interest.
■
(11) Hu, J.; Kong, B.; Liu, Y.; Xu, X. B.; Zhao, Y.; Gong, P. Highly
Stereoselective Synthesis of Imidazolidines through the Palladium(0)-
Catalyzed Three-Component Reaction of 2,3-Allenylamines, Organic
Halides, and Imines. ChemCatChem 2017, 9 (3), 403−406.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (No. 81903469) and Weifang
Science and Technology Development Plan Project (No.
2019GX029).
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DOI: 10.1021/acs.organomet.9b00656
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